Antipsychotics-1: Intro PDF

Antipsychotics-1; Intro PCOL825A/Fall 2023 Acosadora 4:01 La Misa Negra official MV 1 1 Schizophrenia-Introduction ! A “psychotic” disorder ! “Psychotic” meaning being out-of-touch with reality ! Previously psychoses were classified as “functional” vs “medical” • “functional” generally referring...

Antipsychotics-1; Intro PCOL825A/Fall 2023 Acosadora 4:01 La Misa Negra official MV 1 1 Schizophrenia-Introduction ! A “psychotic” disorder ! “Psychotic” meaning being out-of-touch with reality ! Previously psychoses were classified as “functional” vs “medical” • “functional” generally referring to a psychiatric cause • “medical” referring to an “organic” cause, such as brain injury or drug abuse ! However this distinction was more important when psychiatric disorders were regarded as disorders of the “mind” as if there was not an “organic” basis to consciousness ! Increasingly the “organic” basis of psychiatric disorders is being understood as a disorder of the biochemistry of the brain 2 2 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 1 An>psycho>cs-1; Intro PCOL825A/Fall 2023 Schizophrenia as Defined in the “Diagnostic & Statistical Manual of Mental Disorders” (DSM-5) ! Two or more of the following symptoms present for most of a month • hallucinations: sensory perceptions in the absence of a physical stimulus; typically auditory (hearing voices, 3rd person running commentaries, one or more voices arguing, etc.) • delusions: fixed false beliefs; typically involving persecution, surveillance, poisoning, thought and/or mind control by another person or object • disorganized speech: lack of logical continuity (loose associations) Dear Dr. Russell a letter 3 3 Schizophrenia as Defined in the “Diagnostic & Statistical Manual of Mental Disorders” (DSM-5) ! Two or more of the following symptoms-continued • grossly disorganized or catatonic behavior: agitated and/or purposeless movement; immobile, not responding to stimuli; “waxy” flexibility • negative symptoms: diminished emotional responses (flat or blunted affect); alogia; apathy; anhedonia; avolition befamiliar with these terms 4 4 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 2 Antipsychotics-1; Intro PCOL825A/Fall 2023 Schizophrenia as Defined in the “Diagnostic & Statistical Manual of Mental Disorders” (DSM-5) ! Noticeable deterioration in social or occupational functioning • at work; interpersonal (family); personal (self care/hygiene) ! Symptoms present for at least 6 months • schizophreniform, 1-6 months • “brief psychotic disorder” < 1 month ! Exclusion criteria • schizoaffective or other mood disorders • prescription drug/substance abuse • other medical conditions; age??? 5 5 Schizophrenia-General Classification of Symptoms ! Most antipsychotics are very effective for relieving positive symptoms ! But are much less so with respect to the negative and cognitive symptoms; sometimes making them worse 6 6 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 3 Antipsychotics-1; Intro PCOL825A/Fall 2023 Schizophrenia-Onset and General Characteristics ! Initial symptoms typically appear during adolescence or early adulthood (dementia praecox) • males: 15-24 yrs • females: 25-34 yrs ! Although neurological “soft signs” may present earlier • sensory integration; motor coordination; sequencing of complex motor tasks ! Most obvious are the positive symptoms that occur during overt psychosis, which tends to be episodic with periods of more or less normal functioning in between ! Not all acute psychotic episodes (breaks) result in long term disease you • ~25% one acute episode-no impairment • ~25% more than one episode-no significant impairment • ~50% more than one episode-various degrees of significant impairment 7 7 Schizophrenia-Onset and General Characteristics ! “Residual Features” are characteristic of schizophrenia, even in the absence of overt psychosis • anxiety; suspiciousness; poor judgement; depression ! There is significant morbidity and mortality • average life expectancy is 12-15 years less • a major risk factor is suicide; ~5% (500 x the general population) Radioactive live SNL 4:49 Im agine Dragons w/ Kendrick Lam ar 8 8 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 4 An>psycho>cs-1; Intro PCOL825A/Fall 2023 Schizophrenia-Cause?? ! The cause of schizophrenia is essentially unknown ! However, since all presently effective antipsychotics are dopaminergic receptor antagonists; it is generally believed that disorders in the normal functioning of dopaminergic neural pathways are involved ! But, it appears that glutamatergic pathways may also be involved • phencyclidine (angel dust) and ketamine are glutamate receptor antagonists that can produce psychotic symptoms that are similar to those of schizophrenia • genetic “knockout” of glutamate receptors in mice produce symptoms similar to those observed in schizophrenia, which can be reversed with antipsychotics ! Estrogen may have a “protective” role • the onset of schizophrenia is delayed in women • the symptoms are generally less severe • there is a 2nd peak of diagnoses after menopause 9 9 Antipsychotic Drugs-Introduction ! Their discovery came about in an effort by the Rhône-Poulenc Co. to develop antihistamines starting in 1933. ! In 1947 they prepared promethazine, a phenothiazine, that was found to cause relaxation and “indifference” in patients undergoing surgical procedures. ! Chlorpromazine was subsequently synthesized in 1950 and was found to be even more effective in this regard. ! Because of its calming effect, without excess sedation, in 1952 it was tested in psychotic patients with dramatic results. ! Chlorpromazine was approved by the FDA in 1955 for the treatment of emesis, but was quickly adopted by psychiatrists for the treatment of schizophrenia. promethazine anti-histamine (H1) chlorpromazine phenothiazine an5psycho5c 10 10 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 5 Antipsychotics-1; Intro PCOL825A/Fall 2023 Antipsychotic Drugs-Introduction ! Chlorpromazine and subsequent antipsychotics alleviated psychotic symptoms by a calming effect involving an apparent “indifference” to aversive stimuli without excess sedation or loss of consciousness. ! The term “neuroleptic” came into play referring to these drugs ability to slow motor activity, decrease emotionality and reactivity to stimuli ! Several chemical classes were initially developed (phenothiazines, butyrophenones, thioxanthenes), but one property they all shared was their ability to block (antagonize) dopamine receptors 11 11 Antipsychotic Drugs-Dopamine Receptors ! There are five subtypes of dopamine receptors • they are all in the family of G-protein-coupled receptors ! Antagonism of the D2 subtype appears to be clinically important for the beneficial effects (reduced positive symptoms) of antipsychotic drugs ! However, antagonism of dopamine receptors is also responsible for extrapyramidal movement disorders and neuroendocrine side effects 12 12 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 6 Antipsychotics-1; Intro PCOL825A/Fall 2023 Antipsychotic Drugs-Other Neurotransmitter Receptors ! In addition to blocking dopamine receptors, antipsychotics antagonize other classes of receptors to produce various “off-target” effects, which are generally adverse, but not always • alpha-1: postural hypotension; impaired ejaculation/orgasm • muscarinic: anticholinergic (dry mouth, sedation, urinary retention, etc.) • histamine H1: sedation; weight gain • serotonin 5HT1A: decreased affect (depression, negative symptoms worse) • serotonin 5HT2A: improved cognitive function? • serotonin 5HT2C: improved cognitive function? possible weight gain 13 13 Antipsychotic Drugs-Effects on Dopaminergic Pathways Effects of Antipsychotic Drugs on Various Dopaminergic Pathways in the Brain Pathway Yi nigrostriatal (substantia nigra to Function Drug Effects extrapyramidal system movement disorders mesolimbic (midbrain to limbic areas-nucleus accumbens) arousal, sensory processing, behavior control of hallucinations, delusions, i.e. antipsychotic mesocortical (midbrain to prefrontal cortex) thinking, communication, social interactions, behavior tuberoinfundibular control of prolactin secretion basal ganglia) (hypothalamus to pituitary) increased prolactin secretion, other hypothalamic 14 14 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 7 An#psycho#cs-2; Bipolar PCOL825A/Fall 2023 Antipsychotic Drugs-Their Impact ! Before the introduction of the antipsychotic drugs, there were no effective treatments for schizophrenia and what existed were crude, and in many cases horrifying • trepanation • exorcism (the Church) or extermination (Nazis) • hydrotherapy, insulin shock, metrazol shock, electro-shock • lobotomy (for which, Antonio Moniz received the 1949 Nobel Prize) ! The incidence of schizophrenia is ~1% and most states had hospitals devoted exclusively to the “treatment” of this disease • Pilgrim State Hospital in N.Y. is but one example Pilgrim State Hospital 16 16 Pilgrim State Hospital, New York • Originally designed to house 12,500 pa8ents on 1,900 acres of land, Pilgrim s8ll holds the record of being the largest psychiatric hospital in the world - its peak pa8ent popula8on at one 8me was 16,000. 17 17 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 1 An#psycho#cs-2; Bipolar PCOL825A/Fall 2023 Antipsychotic Drugs-General Properties ! Antipsychotics generally have rapid calming effects within hours to a few days, but a full therapeutic response may take several weeks ! There are marked differences in the potency of antipsychotics; as well as the range of effective doses Drug chlorpromazine haloperidol risperidone quetiapine Dose Range 100-1,000 2-60 4-16 150-800 10 30 4 5 (mg/day) (fold) ! General approach to first time treatment of schizophrenia • find a dose to control positive symptoms • find a maintenance dose ( ⅓-⅕ of the initial dose) • after 6-12 months tapper and discontinue if no re-immergence of symptoms 22 22 Antipsychotic Drugs-General Properties ! Antipsychotic drugs are categorized into two major groups based on their historical development and pharmacological properties ! The first group is known as the “1st generation” antipsychotics (FGA), but are often referred to as the “typical” or “conventional” antipsychotics ! While the second group was initially referred to as “atypical” but is now being called the “2nd generation” antipsychotics (SGA) 23 23 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 4 An#psycho#cs-2; Bipolar PCOL825A/Fall 2023 Antipsychotic Drugs-General Properties ! An important distinction applied to the FGA was whether they were “low potency” or “high potency” (referring to dopamine receptor blockade) • low potency FGA (eg, chlorpromazine, thioridazine) have relatively lower affinity for dopamine receptors and higher affinity for other receptors (eg, alpha-1, muscarinic, histamine), making them less selective for dopamine receptors • high potency agents (eg, haloperidol, fluphenazine) have relatively higher affinity for dopamine receptors and lower affinity for other receptors, making them more selective for dopamine receptors • low potency agents tend to have more adverse effects related to interactions with non-dopamine receptors (eg, sedation, hypotension, weight gain) • high potency agents tend to have more adverse effects related to blockade of dopamine receptors (eg, movement and neuroendocrine disorders) 24 24 Antipsychotic Drugs-General Properties ! The first of the second generation antipsychotics (SGA) was clozapine • first approved in 1972 clozapine was removed from the market in 1975 because it was found to cause agranulocytosis in ~1% of patients • however following its introduction clozapine found use in the management of treatment resistant patients with generally fewer movement and neuroendocrine side effects • clozapine also appeared to be generally better than most the existing FGA on negative and cognitive symptoms • • thus clozapine was reintroduced in 1989 with strict prescribing guidelines efforts made to develop clozapine-like agents resulted in the introduction of risperidone in 1995, olanzapine in 1996 and quetiapine in 1997 • since then eight additional SGA have been approved 25 25 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 5 Antipsychotics-2; Bipolar PCOL825A/Fall 2023 FDA Approved Antipsychotic Drugs ‡ Recognize “azines” and “dols”. ‡ Withdrawn-cardiac arrhythmias. = low potency = intermediate potency ‡ Generic available. * Primary active metabolite of resperidone. # Close structural analogue of aripiprazole. = high potency 26 26 Specific Properties of SGA Receptor Affinity K e y notation ++++ +++ ++ + NS KD (nM) 0.1-1.0 1-10 10-100 100-1000 > 1000 Abbreviations K e y PA sed EPS hyper P L ? ( ) partial ago n i s t sedatio n extrapyramidal sympto m s hyperprolactinemia not conclusive based on limited data 27 27 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 6 Antipsychotics-2; Bipolar PCOL825A/Fall 2023 Specific Properties of SGA 28 28 Antipsychotic Drugs-General Properties ! SGA are distinguished from FGA by having generally higher affinity for 5HT2A receptors relative to D2 receptors • their affinity for other neurotransmitter receptors (alpha, muscarinic, histamine, etc) varies according to the individual drug • some SGA are D2 receptor partial agonists (aripiprazole, cariprazine) ! SGA have been marketed as being more effective and safer than FGA • this generalization is questionable under “real-world” conditions and is more dependent upon the properties of the individual drugs • SGA cause fewer movement disorders than high potency FGA; but there appears to be little difference between SGA and low potency FGA 29 29 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 7 An#psycho#cs-2; Bipolar PCOL825A/Fall 2023 Antipsychotic Drugs-Adverse Effects ! The major adverse effects of antipsychotics are movement disorders, known as Extra-Pyramidal Symptoms (EPS) 8k ! EPS arise from the blockade of dopamine receptors in the nigrostriatal pathway (from the substantia nigra to the striatum-basal ganglia) formpolamersthat areblack ! Three of these movement disorders tend to occur early in therapy DA receptors here (days to weeks) • pseudo-parkinsonism • akathisia • acute dystonia dopaminecan musclespasm DA made here ! The fourth usually occurs later in therapy (months to years) and is the most problematic • tardive dyskinesia 30 Latemovement disorder 30 Antipsychotic Drugs-Adverse Effects EPS Effect Incidence* Symptoms Treatment pseudoparkinsonism 10-20% muscle rigidity, tremors, shuffling gait, drooling anti-cholinergics (NOT levodopa) akathisia 10-20% acute dystonias 2-10% spasm of facial muscles (tongue, face, neck) anti-cholinergics benzodiazepines tardive dyskinesia 20-40% involuntary movements of tongue, lips, facial muscles no effective treatment unpleasant restlessness, beta-blockers urge to move, esp the legs benzodiazepines anxiety, dysphoria *with low potency FGA; generally lower with selected SGA; lowest with clozapine dystonia akathisia tardive symp 31 31 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 8 Antipsychotics-2; Bipolar PCOL825A/Fall 2023 VMAT-2 Inhibitors for Tardive Dyskinesia H3CO valbenazine H3CO H3CO H3CO tetrabenazine (racemic) (TBZ) H3CO D3CO H3CO D3CO Deutetrabenazine this is tetrabenazine (deuterated) Deuterium is one of two stable isotopes of hydrogen. It differs from “hydrogen” (pro:um) by having a proton and neutron, whereas pro:um only has a proton. The D---C bond is stronger than the H---C bond, which decreases the O-demethyla;on of TBZ and gives deutetrabenazine a longer half-life (~2-fold). 32 32 VMAT-2 Inhibitors for Tardive Dyskinesia ! Tetrabenazine (Xenazine®) • Known since the 1950’s and priced at $42 per bottle of 112 tablets until 2008 when it received FDA approval as Xenazine® and the price went to $21,000 per bottle!!! ! Valbenazine (Ingressa®) • How is this possible?? See slide on next page. FDA approved in 2017 for treatment of tardive dyskinesia ! Deutetrabenazine (Austedo®) • FDA approved in 2017 for treatment of Huntington’s chorea and tardive dyskinesia • 1st deuterated drug to be approved for human use General Properties of all these Drugs • selective inhibitors of the vesicular monoamine transporter-2 (VMAT-2) • decreases dopamine, serotonin, norepinephrine, histamine in the CNS • Adverse Effects: sleepiness (~30%), difficulty sleeping (~20%), depression (~20%), decreased blood pressure, dizziness, akathisia (~5%), hyperprolactinemia, QT-prolongation, neuroleptic malignant syndrome, drug-drug interactions • Black Box Warning for depression/suicidal ideation 33 33 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 9 An#psycho#cs-2; Bipolar PCOL825A/Fall 2023 The Orphan Drug Act of 1983 and the Inherent Nature of a Profit-Based Health Care System (greed) make it Possible to Place Profits over Humanitarian Needs • Orphan Drug Act was passed by Congress in 1983. • It was written to provide an economic incentive for drug companies to develop drugs for rare diseases*, which by their very nature (rare) had a limited potential for large profits. • Among the incentives were 7 years of “exclusivity” (monopoly) even for drugs, such as generics, that were otherwise unpatentable. • Tetrabenazine (TBZ), as Nitoman®, had been marketed as a generic drug by Cambridge Labs in Canada since 1996 for the treatment of several hyperkinetic movement disorders including Huntington’s chorea (HC) and tardive dyskinesia. It was priced at ~$42/bottle. • In August 2008 Biovail Corp received Orphan Drug approval for TBZ as Xenazine® for the treatment of HC, which gave it exclusivity until 2015. They priced it at ~$6,000/bottle. • In May 2009 Biovail acquired Cambridge Lab’s entire portfolio for TBZ products, meaning that Biovail was now the exclusive supplier of TBZ. • In 2010 Biovail was acquired by Valeant Pharmaceuticals and the price of TBZ continued to climb, reaching ~$21,000/bottle by 2015, when it went “generic.” • But since Valeant was the only supplier of TBZ, they have continued to maintain a very high and unreasonable price. *Affecting fewer than 200,000 people 34 34 General Strategies for Handling Tardive Dyskinesia • Use the least amount of drug for the shortest duration • Second Generation Antipsychotics (SGA) low affinity D2 dopamine receptor antipsychotics • Over First Generation Antipsychotics (FGA), especially high affinity agents • Discontinue antipsychotic slowly, possibly switch to SGA (clozapine preferred) 35 35 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 10 An#psycho#cs-2; Bipolar PCOL825A/Fall 2023 Antipsychotic Drugs-Adverse Effects ! Hyperprolactinemia is another adverse effect of many antipsychotics • prolactin secretion by the pituitary is under tonic inhibitory control by dopamine produced in the hypothalamus (the tubero-infundibular pathway) • blocking DA receptors in the pituitary, therefore, increases prolactin secretion • patients may be asymptomatic, or experience gynecomastia, oligo- or amenorrhea, sexual dysfunction, acne, hirsutism, infertility, etc. • prolonged hyperprolactinemia is associated with loss of bone mineral density, which can lead to osteoporosis and increased risk of hip fractures ! Sedation, orthostatic hypotension, dry mouth/urinary retention, etc., associated with blockade of histamine H1, alpha-1, muscarinic receptors, etc. 36 36 Antipsychotic Drugs-Adverse Effects ! Weight gain and the development of metabolic syndrome • common adverse effect; appears to be associated with histamine H1 receptor antagonism; perhaps serotonin 5-HT2C • weight gain can be rapid and difficult to control • insulin resistance and dyslipidemia often follow the weight gain Es#mated Weight Gain at 10 Weeks (2½ months) 9 7 4 2 ch lor ris pe r -2 ido ne pr om az ine se rM nd ole th ior ida zin e ola nz ap ine clo za pin e 0 pla ce bo m oli nd on e zip ra sid on e flu ph en az ine ha lop er ido l Change in Body Weight (lbs) 11 37 37 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 11 Antipsychotics-2; Bipolar PCOL825A/Fall 2023 Antipsychotic Drugs-Adverse Effects ! Increased risk of death in elderly patients being treated for dementiarelated psychosis Black Box Warning • increased risk is ~2-fold • applies to both 1st and 2nd generation antipsychotics • involves increased sudden cardiac death and stroke • (presently there are NO medications with FDA approval for the treatment of dementia-related psychosis) ! Increased risk of seizures (0.5-1%) • all antipsychotics lower the “seizure threshold” with greater risk associated with the more sedating antipsychotics (especially clozapine) • should be used with caution in patients with a history of seizures ! Increased risk of cardiac arrhythmias (~2-fold) • all antipsychotics delay ventricular repolarization (increased QT-interval) by blocking potassium channels (IKr) • avoid combining with other drugs that increase the QT-interval 38 38 Antipsychotic Drugs-Adverse Effects ! Neuroleptic malignant syndrome • rare (0.5-1%); but significant mortality (5-20%) • 80% of cases occur in first 2 weeks of treatment, but may occur later as well • similar to serotonin syndrome: fever, severe muscle rigidity, agitation/delirium • treatment is supportive; dantrolene (Ca2+ antagonist) for rigidity; bromocriptine (dopamine receptor agonist) high fever 39 39 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 12 Antipsychotics-2; Bipolar PCOL825A/Fall 2023 40 40 Bipolar Disorder ! Defined by the presence of a manic episode ! But the initial presentation may be depression; which is important to recognize, because anti-depressants (esp TCAs) can cause a sudden switch from depression to hypomania or overt mania ! Bipolar disorder is categorized as follows: • type-1: severe mania w/wo psychotic features; functional impairment and/or hospitalization; major depression • type-2: hypomania; moderate or major depression • cyclothymic: hypomania; mild or moderate depression • bipolar not otherwise specified (NOS) 41 41 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 13 An#psycho#cs-2; Bipolar PCOL825A/Fall 2023 Drugs Used in the Treatment of Bipolar Disorder ! Drug treatment depends on how the patient initially presents; for example, with mania or depression ! The goal is to eliminate or reduce the severity of the mood swings through the use of “mood stabilizers” which include: • lithium: the “gold standard” but limited by a narrow therapeutic index • various anticonvulsants including valproic acid, carbamazepine, topiramate, gabapentin and lamotrigine Vincent Van Gogh • various antipsychotics including haloperidol and virtually all “atypical” or 2nd generation antipsychotics, such as olanzapine and quetiapine • lumateperone was approved in 2021 for bipolar depression; lamotrigine has some efficacy as well, but its use is off-label 42 42 The Pharmacological Properties of Lithium ! Used since the 1950’s for the treatment of bipolar disorder, lithium is probably still the best for reducing risk of suicide ! But lithium has a narrow therapeutic index (potentially fatal plasma concentrations are only 2-3 times therapeutic levels) ! Lithium is known to inhibit inositol monophosphatase and glycogen synthase kinase (GSK), but how this translates into a therapeutic benefit is presently unknown Ludwig van Beethoven ita ( e xc (i n h i b tory) itory) 43 43 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 14 Antipsychotics-2; Bipolar PCOL825A/Fall 2023 Adverse Effects of Lithium (at therapeutic concentrations) ! reproductive: risk of cardiac malformations in 1st trimester of pregnancy • the incidence is often stated to be ~ 10%, but it is probably closer to ~1%* • the benefits of lithium may nevertheless merit its use during pregnancy • risk can be minimized by keeping doses below 900 mg/day ! gastrointestinal: nausea, vomiting, diarrhea ! neurological: fatigue, slurred speech, hand tremor ! renal: polyuria, nocturia and excessive thirst ! thyroid: hypothyroidism, goiter ! increased dietary sodium decreases efficacy (and toxicity) of lithium ! sodium depletion (low Na+ diets, excessive sweating) increases the retention and toxicity of lithium *N Engl J Med 376:2245-2254, 2017 Kurt Cobain 44 44 45 45 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 15